Refine
Year of publication
Document Type
- Article (15825)
- Part of Periodical (2728)
- Working Paper (2352)
- Preprint (2083)
- Doctoral Thesis (2065)
- Book (1736)
- Part of a Book (1071)
- Conference Proceeding (752)
- Report (471)
- Review (165)
Language
- English (29413) (remove)
Has Fulltext
- yes (29413) (remove)
Keywords
- taxonomy (744)
- new species (444)
- morphology (174)
- Deutschland (142)
- Syntax (125)
- Englisch (120)
- distribution (117)
- biodiversity (101)
- Deutsch (98)
- inflammation (97)
Institute
- Medizin (5346)
- Physik (3819)
- Wirtschaftswissenschaften (1915)
- Frankfurt Institute for Advanced Studies (FIAS) (1760)
- Biowissenschaften (1550)
- Center for Financial Studies (CFS) (1492)
- Informatik (1401)
- Biochemie und Chemie (1090)
- Sustainable Architecture for Finance in Europe (SAFE) (1069)
- House of Finance (HoF) (707)
This article examines whether autonomy as an educational aim should be defended at the global scale. It begins by identifying the normative issues at stake in global autonomy education by distinguishing them from the problems of autonomy education in multicultural nation-states. The article then explains why a planet-wide expansion of the ideal of autonomy is conceivable on the condition that the concept of autonomy is widened in a way that renders its precise meaning flexibly adjustable to a variety of distinct social and cultural contexts. A context-transcendent, core meaning of autonomy remains in place, however, according to which a person is only autonomous if she relates to the values and goals that direct her life in a way so that she sees them as her own and is able to identify and critically assess her principal reasons for action. Finally, the article addresses two challenges to the global expansion of autonomy education: the objection that autonomy is presently not the most important educational aim and the objection that global autonomy education is a form of cultural imperialism. It finds both objections wanting.
Introduction
(2020)
As a result of globalization, the number of people living outside of their countries of origin is on the rise. Among them are children of primary and secondary school age of varying socio-economic backgrounds. This article addresses the education-related challenges that children in such circumstances face. I first identify two principles – an educational adequacy principle and a presumption of responsibility on the part of a host country for meeting children’s educational
needs – which are widely employed to guide national policy decisions on educational content and the distribution of educational resources. I then discuss a number of problems that students living abroad face which, I argue, policies devised on the basis of these principles either systematically overlook or, in some cases, exacerbate. Finally, I offer two alternative principles – a cosmopolitan revision of the first and a replacement for the second with a focus on collective responsibility – designed to promote education policies better suited to a globalized world which might help to alleviate the barriers to success commonly encountered by children learning abroad.
This paper examines and rejects two normative justifications for low-fee private schools (LFPS), whose expansion throughout the Global South in recent years has been significant. The first justification – what I shall call the ideal thesis – contends that LFPS are the best mechanism to expand access to quality education, particularly at the primary level, and that the premise of their success is that they reject educational equality and state intervention in educational affairs, traditionally associated with public schools, embracing instead educational adequacy and unregulated markets for education. Against this thesis, the paper argues that an ideal educational arrangement must not do away with educational equality and some degree of state interference. The other justification for LFPS – the secondbest thesis – contends that although LFPS do not represent the ideal state of affairs, they nonetheless bring us a step closer to the ideal of universal primary education; they are a ‘realistic’ approximation to that goal. Against the second-best thesis, the paper argues that this justification commits the approximation fallacy: by deviating from the ideal educational arrangement LFPS may obstruct rather than facilitate its achievement.
This contribution develops a defence of a universalist conception of Global Citizenship Education (GCE) against three prominent critiques, which are, among others, put forward by postcolonial scholars. The first critique argues that GCE is essentially a project of globally minded elites and therefore expressive both of global educational injustices and of the values and lifestyles of a particular class or milieu. The second critique assumes that GCE is based on genuinely ‘Western values’ (e.g., in the form of a conception of human rights or conceptions of rationality or the self), which are neither universally accepted nor universally valid and therefore unjustly forced on members of non-Western cultures and societies. GCE, according to this critique, is assumed to be another version of the educational justification of a hegemonic and unjust global Western regime. The third critique focuses on the epistemological preconditions of GCE. It assumes that GCE relies on a particular, culturally embedded ‘Western epistemology,’ which perpetuates historically grown global educational and epistemic injustices by dominating and subjugating alternative epistemological approaches. With respect to the first critique I argue that it is to a certain extent sociologically plausible, but wrong when it is applied to the educational and political legitimacy of GCE. The second critique overestimates the consensus within the ‘Western tradition’ and underestimates the transnational dissemination of universalist ideals and values as well as its own reliance on universalist validity claims. I argue that in order to provide a plausible criticism of historically grown global educational and political injustices, it is imperative for GCE to integrate central insights provided by the postcolonial critique, without giving up on universalist ideals and values. The third critique is, according to my argumentation, based on flawed epistemological assumptions, which do not withstand critical scrutiny. Instead of identifying epistemic and scientific claims as the expressions of a particular ‘culture’ or geographical location (the ‘West’), I defend the position that philosophical and scientific research should ideally be conceived as a democratic and universalist project, whose emancipatory potential can only be realized on the basis of a universalist epistemology.
This paper explores how University as social entity has great potential to confront epistemic injustices by expanding epistemic capabilities. To do this, we primarily follow the contributions of scholars such as Miranda Fricker and José Medina. The epistemic capabilities and epistemic injustice nexus will be explored via two empirical cases: the first one is an experience developed in Lagos (Nigeria) using participatory video; the second is a service learning pedagogical strategy for final year undergraduate students conducted at Universidad de Ibagué (in Colombia). The Lagos experience shows how participatory action-research methodologies could promote epistemic capabilities and functioning, making it possible for the participants to generate interpretive materials to speak of their own realities. However, this experience is too limited to address testimonial and hermeneutical injustice. The Colombian experience is a remarkable experience that is building epistemic capabilities among students and other local participants. However, there is a hermeneutical and structural injustice that tends to give more value to disciplinary and codified knowledge at the expense of experiential and tacit knowledge.
Investigation of co-translational protein folding using cryo-EM and solid-state NMR enhanced by DNP
(2020)
Die zelluläre Proteinbiosynthese findet am Peptidyltransferase-Zentrum innerhalb der großen ribosomalen Untereinheit statt. Die neu synthetisierte Polypeptidkette passiert den ribosomalen Exit-Tunnel, der 80-100 Å lang und 10-20 Å breit ist. Proteinfaltung findet kotranslational statt, während die Peptidkette durch den ribosomalen Tunnel geschleust wird. Zu welchem Ausmaß die Proteine ihre native Struktur noch am Ribosom gebunden annehmen, steht im Fokus aktueller Studien. Verschiedene Methoden, die naszierende Proteinkette am Ribosom zu arretieren und die Faltung des Proteins untersuchen zu können, wurden entwickelt. Zur Herstellung von Ribosom naszierenden Proteinkomplexen (RNCs) in vivo werden Arrestierungspeptide (APs) verwendet. Ein oft genutztes AP ist die 17 Aminosäuren lange SecM Sequenz des E. coli Sekretionsmonitors, das C-Terminal an das zu untersuchende Protein kloniert werden kann und dadurch die Peptidkette am Ribosom behält. RNCs wurden mittels verschiedener Methoden untersucht, einschließlich Proteolyse-Experimenten, enzymatischen Aktivitätsmessungen, FRET, Cryo-EM und NMR-Spektroskopie. Alle Methoden zeigten auf, dass sich die Proteine kotranslational falten und auch am Ribosom eine funktionale Struktur annehmen können. Außerdem konnte eine Peptidkette eine α-Helix innerhalb des Ribosoms ausbilden. Ebenso wurden nicht-native kompakte Strukturen innerhalb der Vestibule detektiert.
Die Translation ist ein nicht-uniformer Prozess und der genetische Code degeneriert mit bis zu sechs Codons, die eine einzelne Aminosäure kodieren. Die Verteilung dieser synonymen Codons ist nicht zufällig und sie werden mit verschiedenen Frequenzen innerhalb eines ORFs verwendet. Codons mit einer höheren tRNA Häufigkeit werden schneller eingebaut als Codons, die seltener verwendet werden. Diese seltenen Codons sind häufig zwischen Proteindomänen oder Sekundärstrukturelementen platziert und könnten daher zur Separierung von Faltungsevents dienen. Dass der Austausch von synonymen Codons nicht ohne Folgen ist, zeigten verschiedene Studien. Buhr et al. (2016) zeigte, dass der synonyme Austausch die Translationsgeschwindigkeit, aber auch die Proteinkonformation des bovinen Augenlinsenproteins γB crystallin (GBC) beeinflusst. Während die unmodifizierte Gensequenz aus B. taurus in E. coli langsamer translatiert wurde und zu einem vollständig reduzierten GBC Protein (U) führte, wurde die harmonisierte Genvariante, die der Codon-Verwendung in E. coli angepasst war, schneller exprimiert und resultierte in einem teilweise oxidierten GBC Protein (H). Dieser Befund war der Ausgangspunkt für diese Doktorarbeit.
Die gemessenen Oxidationsunterschiede basieren auf der unterschiedlichen Translationsgeschwindigkeit der beiden Gensequenzen. Die N-terminale Domäne (NTD) des Zweidomänen-Proteins GBC enthält sechs der insgesamt sieben Cysteinreste. Nur in dieser Domäne wurde Oxidation detektiert und die drei Cysteine Cys18, Cys22 und Cys78 bilden eine Ansammlung mit einem Abstand von 5.4-6.4 Å. Um zu untersuchen, ob die Unterschiede bereits nach der Translation der NTD ausgebildet werden, wurde ein Ein-Domänen-Konstrukt hergestellt. Dieses Konstrukt beinhaltete die Aminosäuren 1-82, aber nicht den Peptidlinker, der beide Domänen verbindet. Allerdings wurden bei der Translation der ersten 70 Aminosäuren die meisten Translationspausen detektiert. Das 2D 1H-15N HSQC wies anhand der unterschiedlichen chemischen Verschiebung der Signale auf eine gefaltete Proteinstruktur hin. Daher konnte sich die NTD ohne Beteiligung der CTD eigenständig falten. Zugabe von DTT zu beiden Proteinvarianten U und H führte zu keinem messbaren Effekt. Im Gegensatz zu dem Volllängen-Protein, in dem die Variante H teilweise oxidiert war, war die NTD der Variante H vollständig reduziert.
Zusätzlich sollte geklärt werden, ob auch mögliche Disulfidbrücken im Inneren des Ribosoms ausgebildet werden können. Dann könnte in beiden Genvarianten eine anfängliche Disulfidbrücke ausgebildet werden und durch die unterschiedliche Translationsgeschwindigkeit die Disulfidbrücke in der langsamen Genvariante im E. coli Zytosol reduziert werden, während diese in der schneller translatierten Variante von der CTD geschützt wird. Um zu untersuchen, ob in der Tat Disulfidbrücken im ribosomalen Tunnel ausgebildet werden können, wurden GBC-Fragmente mittels der SecM Sequenz an das Ribosom arretiert und diese RNCs mittels theoretischer Simulation, Festkörper-NMR, Massenspektrometrie und Cryo-EM gemessen.
Theoretische Simulation mittels flexible-mecanno zeigten, dass der ribosomale Tunnel groß genug für die Ausbildung verschiedenster Disulfidbrücken ist. In einem U32SecM Konstrukt, das vier Cysteine und die SecM Sequenz beinhaltet, konnten alle theoretisch möglichen Disulfidbrücken gebildet werden.
...
This paper addresses the phenomenon of climate-induced displacement. I argue that there is scope for an account of asylum as compensation owed to those displaced by the impacts of climate change which needs only to appeal to minimal normative commitments about the requirements of global justice. I demonstrate the possibility of such an approach through an examination of the work of David Miller. Miller is taken as an exemplar of a broadly ‘international libertarian’ approach to global justice, and his work is a useful vehicle for this project because he has an established view about both responsibility for climate change and about the state’s right to exclude would-be immigrants. In the course of the argument, I set out the relevant aspects of Miller’s views, reconstruct an account of responsibility for the harms faced by climate migrants which is consistent with Miller’s views, and demonstrate why such an account yields an obligation to provide asylum as a form of compensation to ‘climate migrants.’
This paper discusses two possible difficulties with Catherine Lu’s powerful analysis of the moral response to our shared history of colonial evil; both of these difficulties stem from the rightful place of shame in that moral response. The first difficulty focuses on efficacy: existing states may be better motivated by shame at the past than by a shared duty to bring about a just future. The second focuses on equity: it is, at the very least, possible that shame over past misdeeds ought to be brought into the conversation about present duties, in a manner more robust than Lu’s analysis allows.
In Justice and Reconciliation in World Politics Catherine Lu endorses the idea that those who contribute to the reproduction of structural injustice have responsibilities to address that injustice (Lu, 2017). However, in the book, Lu does not explore the grounds and justification for recognising such a responsibility. In order to address this deficit, this paper proposes that those likely to contribute to the reproduction of structural injustice, in the future, have precautionary duties, in the present, that require them to take action aimed at preventing their future contribution. It is proposed that these ‘collectivization duties’ (Collins, 2013) require them to act responsively with a view to forming a collective that can end the structural injustice in question. This account recommends a collective-action solution alongside recognising that each socially connected agent is obliged to act. However, it does not entail that amorphous groups bear responsibilities and is appropriate in its attribution of blame, thus avoiding both Nussbaum’s (2011) critique of perpetually forward-looking accounts and the ‘agency objection’ (Wringe, 2010).
This article analyzes and criticizes the temporal orientation of Catherine Lu’s theory of colonial redress in Justice and Reconciliation in World Politics. Lu argues that colonial historic injustice can, with few exceptions, justify special reparative measures only if these past injustices still contribute to structural injustice in contemporary social relations. Focusing on Indigenous peoples, I argue that the structural injustice approach can and should incorporate further backward looking elements. First, I examine how Lu’s account has backward-looking elements not present in other structural injustice accounts. Second, I suggest how the structural injustice approach could include additional backward-looking features. I presuppose here, with Lu, that all agents connected to an unjust social structure have a forwardlooking political responsibility to reform this structure, regardless of their relation (or lack thereof) to victims or perpetrators of historic injustice. However, I suggest that agents with connections to historic injustice can occupy a social position that makes them differently situated than other agents within that same structure, leading to differences in how these agents should discharge their forward-looking responsibility and differentiated liability for failure to do so. Third, I argue that Lu obscures the importance of rectifying material dispossession. Reparations, pace Lu, can be justified beyond a minimum threshold of disadvantage. Theorists of settler colonialism and Indigenous scholars show how the dispossession of Indigenous land can be seen as a structure that has not yet ended. I conclude by arguing that rectification can be a precondition for genuine reconciliation.
Structural alienation: Lu's structural approach to reconciliation from within a relational framework
(2019)
In Justice and Reconciliation in World Politics Catherine Lu argues that structural reconciliation, rather than interactional reconciliation, ought to be the primary normative goal for political reconciliation efforts. I suggest that we might have good reason to want to retain relational approaches – such as that of Linda Radzik – as the primary focus of reconciliatory efforts, but that Lu’s approach is invaluable for identifying the parties who ought to bear responsibility for those efforts in cases of structural injustice. First, I outline Lu’s analysis of reconciliation, where she argues for the normative priority of structural approaches within the global political sphere, and propose that it will be useful to identify whether or not a relational account could instead identify underlying structural injustices. Second, I examine one particular relational account of reconciliation (based on Radzik’s account of atonement) and argue that this type of account brings to light underlying structural injustices of the kind Lu is concerned with. Finally, I identify an issue for relational accounts in identifying relevant responsible parties for reconciliation before returning to Lu’s structural account to address this gap.
Traditionally, in deciding whether some strategy or action in war is proportionate and necessary and thus permissible both international law and just war theory focus exclusively on civilian deaths and the destruction of civilian infrastructure. I argue in this paper that any argument that can explain why we should care about collateral killing and damage to infrastructure can also explain why collateral displacement matters. I argue that displacement is a foreseeable near-proximate cause of lethal harm to civilians and is relevant for proportionality and necessity calculi. Accepting my argument has significant consequences for what we are permitted to do in war and for what obligations we have towards refugees that result from our actions in war.
Moral refugee markets
(2018)
States are increasingly paying other states to host refugees. For example, in 2010 the EU paid Libya €50 million to continue hosting the refugees within its borders, and five years later Australia offered Cambodia $31.16 million to accept asylum seekers living in Naru. These exchanges, which I call ‘refugees markets,’ have faced criticism by philosophers. Some philosophers claim the markets fail to ensure true protection, and are demeaning, expressing just how much refugees are unwanted. In response, some have defended refugee markets, claiming they can ensure refugees have protection and are not demeaned. I argue that many markets do demean refugees, and therefore have moral costs, but can still be all-things-considered preferable to alternative schemes if they protect refugees more than these alternative schemes.
This essay develops, within the terms of the recent New York Declaration, an account of the shared responsibility of states to refugees and of how the character of that responsibility effects the ways in which it can be fairly shared. However, it also moves beyond the question of the general obligations that states owe to refugees to consider ways in which refugee choices and refugee voice can be given appropriate standing with the global governance of refuge. It offers an argument for the normative significance of refugee’s reasons for choosing states of asylum and linked this to consideration of a refugee matching system and to refugee quota trading conceived as responsibility-trading, before turning to the issue of the inclusion of refugee voice in relation to the justification of the norms of refugee governance and in relation to the institutions and practices of refugee governance through which those norms are given practical expression.
The issue of statelessness poses problems for the statist (or nationalist) approach to the philosophy of immigration. Despite the fact that the statist approach claims to constrain the state’s right to exclude with human rights considerations, the arguments statists offer for the right of states to determine their own immigration policies would also justify citizenship rules that would render some children stateless. Insofar as rendering a child stateless is best characterized as a violation of human rights and insofar as some states have direct responsibility for causing such harm, the problem of non-refugee stateless children points to greater constraints than most statists accept on states’ right to determine their own rules for membership. While statists can ultimately account for the right not to be rendered stateless, recognizing these additional human rights constraints ultimately weakens the core of the statist position.
While global justice theorists heatedly discuss the responsibilities of the affluent and powerful, those states which can legitimately be seen as victims of global injustice have seldom, if ever, been considered as duty bearers to whom responsibilities can be attached. However, recognising agents whose options are constrained not only as victims, but also as duty bearers is necessary as a proof of respect for their agency and indispensable to mobilise the type of action required to alter global injustices. In this article, I explore what responsibilities state officials of dominated states have. I argue that they have the responsibility to resist domination in the name of the dominated states members. While under particular circumstances this responsibility gives rise to a duty to engage in acts of state civil disobedience, under other circumstances state officials of dominated states ought to resist domination in an internal, attitudinal way by recognising themselves as outcome responsible agents.
Fair Trade is under fire. Some critics argue, for instance, that there is no obligation to purchase Fair Trade certified products and that doing so may even be counter-productive. Others worry that well-justified conceptions of what makes trade fair can conflict. Yet others suggest that the common arguments for Fair Trade cannot justify purchasing Fair Trade certified goods, in particular. This paper starts by sketching one common argument for Fair Trade and defends it against this last line of criticism. In particular, it argues that we should purchase Fair Trade certified goods because doing so benefits the poor even though there are other ways to alleviate poverty. It then considers how other common arguments for Fair Trade fare in light of similar criticism and concludes that they may well succeed.
Political realists claim that international relations are in a state of anarchy, and therefore every state is allowed to disregard its moral duties towards other states and their inhabitants. Realists argue that complying with moral duties is simply too risky for a state’s national security. Political moralists convincingly show that realists exaggerate both the extent of international anarchy and the risks it poses to states who act morally. Yet moralists do not go far enough, since they do not question realism’s normative core: the claim that when national security is really at risk, states are allowed to disregard their moral duties. I contend that there is at least one moral duty that states should not disregard even if their inhabitants are at risk of death by military aggression: the duty to reduce extreme global poverty. The reason is that even granting that national security is about securing individuals’ right to life, global poverty relief is about that as well.
Chronic granulomatous disease (CGD) is a primary immunodeficiency, which is diagnosed in most patients between one and three years of age. Here we report on a boy who presented at birth with extensive skin lesions and lymphadenopathy which were caused by CGD. An analysis of the literature revealed 24 patients with CGD who became symptomatic during the first six weeks of life. Although pulmonary complications and skin lesions due to infection were the leading symptoms, clinical features were extremely heterogenous. As follow-up was not well specified in most patients, the long-term prognosis of children with very early onset of CGD remains unknown.
Aging is accompanied by unisensory decline. To compensate for this, two complementary strategies are potentially relied upon increasingly: first, older adults integrate more information from different sensory organs. Second, according to the predictive coding (PC) model, we form “templates” (internal models or “priors”) of the environment through our experiences. It is through increased life experience that older adults may rely more on these templates compared to younger adults. Multisensory integration and predictive coding would be effective strategies for the perception of near-threshold stimuli, which may however come at the cost of integrating irrelevant information. Both strategies can be studied in multisensory illusions because these require the integration of different sensory information, as well as an internal model of the world that can take precedence over sensory input. Here, we elicited a classic multisensory illusion, the sound-induced flash illusion, in younger (mean: 27 years, N = 25) and older (mean: 67 years, N = 28) adult participants while recording the magnetoencephalogram. Older adults perceived more illusions than younger adults. Older adults had increased pre-stimulus beta-band activity compared to younger adults as predicted by microcircuit theories of predictive coding, which suggest priors and predictions are linked to beta-band activity. Transfer entropy analysis and dynamic causal modeling of pre-stimulus magnetoencephalography data revealed a stronger illusion-related modulation of cross-modal connectivity from auditory to visual cortices in older compared to younger adults. We interpret this as the neural correlate of increased reliance on a cross-modal predictive template in older adults leading to the illusory percept.
Background: Polytraumatized patients undergo a strong immunological stress upon insult. Phagocytes (granulocytes and monocytes) play a substantial role in immunological defense against bacteria, fungi and yeast, and in the clearance of cellular debris after tissue injury. We have reported a reduced monocytes phagocytic activity early after porcine polytrauma before. However, it is unknown if both phagocyte types undergo those functional alterations, and if there is a pathogen-specific phagocytic behavior. We characterized the phagocytic activity and capacity of granulocytes and monocytes after polytrauma.
Methods: Eight pigs (Sus scrofa) underwent polytrauma consisting of lung contusion, liver laceration, tibial fracture and hemorrhagic shock with fluid resuscitation and fracture fixation with external fixator. Intensive care treatment including mechanical ventilation for 72 h followed. Phagocytic activity and capacity were investigated using an in vitro ex vivo whole blood stimulation phagocytosis assays before trauma, after surgery, 24, 48, and 72 h after trauma. Blood samples were stimulated with Phorbol-12-myristate-13-acetate and incubated with FITC-labeled E. coli, S. aureus or S. cerevisiae for phagocytosis assessment by flow cytometry.
Results: Early polytrauma-induced significant increase of granulocytes and monocytes declined to baseline values within 24 h. Percentage of E. coli-phagocytizing granulocytes significantly decreased after polytrauma and during further intensive care treatment, while their capacity significantly increased. Interestingly, both granulocytic phagocytic activity and capacity of S. aureus significantly decreased after trauma, although a recovery was observed after 24 h and yet was followed by another decrease. The percentage of S. cerevisiae-phagocytizing granulocytes significantly increased after 24 h, while their impaired capacity after surgery and 72 h later was detected. Monocytic E. coli-phagocytizing percentage did not change, while their capacity increased after 24–72 h. After a significant decrease in S. aureus-phagocytizing monocytes after surgery, a significant increase after 24 and 48 h was observed without capacity alterations. No significant changes in S. cerevisiae-phagocytizing monocytes occurred, but their capacity dropped 48 and 72 h.
Conclusion: Phagocytic activity and capacity of granulocytes and monocytes follow a different pattern and significantly change within 72 h after polytrauma. Both phagocytic activity and capacity show significantly different alterations depending on the pathogen strain, thus potentially indicating at certain and possibly more relevant infection causes after polytrauma.
The adult heart has a limited capacity to replace or regenerate damaged cardiac tissue following severe myocardial injury. Thus, therapies facilitating the induction of cardiac regeneration holds great promise for the treatment of end-stage heart failure, and for pathologies invoking severe cardiac dysfunction as a result of cardiomyocyte death. Recently, a number of studies have demonstrated that cardiac regeneration can be achieved through modulation and/or reprogramming of cardiomyocyte proliferation, differentiation, and survival signaling. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), are reported to play critical roles in regulating key aspects of cardiomyocyte physiologic and pathologic signaling, including the regulation of cardiac regeneration both in vitro and in vivo. In this review, we will explore and detail the current understanding of ncRNA function in cardiac regeneration, and highlight established and novel strategies for the treatment of heart failure through modulation of ncRNAs-driven cardiac regeneration.
The spread of the COVID-19 virus was met by a strict lockdown in many countries around the world, with the closure of all physical activity (PA) facilities and limitations on moving around freely. The aim of the present online survey was to assess the effect of lockdown on physical activity in Italy. Physical activity was assessed using the European Health Interview Survey questionnaire. A total of 1500 datasets were analyzed. Differences between conditions were tested with a chi2-based (χ2) test for categorical variables, and with the Student’s t-test for paired data. A fixed effects binary logistic regression analysis was conducted to identify relevant predictor variables to explain the compliance with World Health Organisation (WHO) recommendations. We found a substantial decline in all physical activity measures. Mean differences in walking and cycling metabolic equivalent of task minutes per week (METmin/week), respectively, were 344.4 (95% confidence interval (95% CI): 306.6–382.2; p < 0.001) and 148.5 (95% CI: 123.6–173.5; p < 0.001). Time spent in leisure time decreased from 160.8 to 112.6 min/week (mean difference 48.2; 95% CI: 40.4–56.0; p < 0.001). Compliance with WHO recommendations decreased from 34.9% to 24.6% (chi2 (1, 3000) = 38.306, p < 0.001, V = 0.11). Logistic regression showed a reduced chance (OR 0.640, 95% CI: 0.484–0.845; p = 0.001) to comply with WHO PA recommendations under lockdown conditions. Measures to promote physical activity should be intensified to limit detrimental health effects.
Research on Podospora anserina unraveled a network of molecular pathways affecting biological aging. In particular, a number of pathways active in the control of mitochondria were identified on different levels. A long-known key process active during aging of P. anserina is the age- related reorganization of the mitochondrial DNA (mtDNA). Mechanisms involved in the stabilization of the mtDNA lead to lifespan extension. Another critical issue is to balance mitochondrial levels of reactive oxygen species (ROS). This is important because ROS are essential signaling molecules, but at increased levels cause molecular damage. At a higher level of the network, mechanisms are active in the repair of damaged compounds. However, if damage passes critical limits, the corresponding pathways are overwhelmed and impaired molecules as well as those present in excess are degraded by specific enzymes or via different forms of autophagy. Subsequently, degraded units need to be replaced by novel functional ones. The corresponding processes are dependent on the availability of intact genetic information. Although a number of different pathways involved in the control of cellular homeostasis were uncovered in the past, certainly many more exist. In addition, the signaling pathways involved in the control and coordination of the underlying pathways are only initially understood. In some cases, like the induction of autophagy, ROS are active. Additionally, sensing and signaling the energetic status of the organism plays a key role. The precise mechanisms involved are elusive and remain to be elucidated.
Mitochondrial F1Fo-ATP-synthase dimers play a critical role in shaping and maintenance of mitochondrial ultrastructure. Previous studies have revealed that ablation of the F1Fo-ATP-synthase assembly factor PaATPE of the ascomycete Podospora anserina strongly affects cristae formation, increases hydrogen peroxide levels, impairs mitochondrial function and leads to premature cell death. In the present study, we investigated the underlying mechanistic basis. Compared to the wild type, we observed a slight increase in non-selective and a pronounced increase in mitophagy, the selective vacuolar degradation of mitochondria. This effect depends on the availability of functional cyclophilin D (PaCYPD), the regulator of the mitochondrial permeability transition pore (mPTP). Simultaneous deletion of PaAtpe and PaAtg1, encoding a key component of the autophagy machinery or of PaCypD, led to a reduction of mitophagy and a partial restoration of the wild-type specific lifespan. The same effect was observed in the PaAtpe deletion strain after inhibition of PaCYPD by its specific inhibitor, cyclosporin A. Overall, our data identify autophagy-dependent cell death (ADCD) as part of the cellular response to impaired F1Fo-ATP-synthase dimerization, and emphasize the crucial role of functional mitochondria in aging.
Background: In clinical practice range of motion (RoM) is usually assessed with low-cost devices such as a tape measure (TM) or a digital inclinometer (DI). However, the intra- and inter-rater reliability of typical RoM tests differ, which impairs the evaluation of therapy progress. More objective and reliable kinematic data can be obtained with the inertial motion capture system (IMC) by Xsens. The aim of this study was to obtain the intra- and inter-rater reliability of the TM, DI and IMC methods in five RoM tests: modified Thomas test (DI), shoulder test modified after Janda (DI), retroflexion of the trunk modified after Janda (DI), lateral inclination (TM) and fingertip-to-floor test (TM).
Methods: Two raters executed the RoM tests (TM or DI) in a randomized order on 22 healthy individuals while, simultaneously, the IMC data (Xsens MVN) was collected. After 15 warm-up repetitions, each rater recorded five measurements.
Findings: Intra-rater reliabilities were (almost) perfect for tests in all three devices (ICCs 0.886–0.996). Inter-rater reliability was substantial to (almost) perfect in the DI (ICCs 0.71–0.87) and the IMC methods (ICCs 0.61–0.993) and (almost) perfect in the TM methods (ICCs 0.923–0.961). The measurement error (ME) for the tests measured in degree (°) was 0.9–3.3° for the DI methods and 0.5–1.2° for the IMC approaches. In the tests measured in centimeters the ME was 0.5–1.3cm for the TM methods and 0.6–2.7cm for the IMC methods. Pearson correlations between the results of the DI or the TM respectively with the IMC results were significant in all tests except for the shoulder test on the right body side (r = 0.41–0.81).
Interpretation: Measurement repetitions of either one or multiple trained raters can be considered reliable in all three devices.
Three AKT serine/threonine kinase isoforms (AKT1/AKT2/AKT3) mediate proliferation, metabolism, differentiation and anti-apoptotic signals. AKT isoforms are activated down- stream of PI3-kinase and also by PI3-kinase independent mechanisms. Mutations in the lipid phosphatase PTEN and PI3-kinase that increase PIP3 levels increase AKT signaling in a large proportion of human cancers. AKT and other AGC kinases possess a regulatory mechanism that relies on a conserved hydrophobic motif (HM) C-terminal to the catalytic core. In AKT, the HM is contiguous to the serine 473 and two other newly discovered (serine 477 and tyrosine 479) regulatory phosphorylation sites. In AKT genes, this regulatory HM region is encoded in the final exon. We identified a splice variant of AKT2 (AKT2-13a), which contains an alternative final exon and lacks the HM regulatory site. We validated the presence of mRNA for this AKT2-13a splice variant in different tissues, and the presence of AKT2-13a protein in extracts from HEK293 cells. When overexpressed in HEK293 cells, AKT2-13a is phosphorylated at the activation loop and at the zipper/turn motif phosphoryla- tion sites but has reduced specific activity. Analysis of the human transcriptome correspond- ing to other AGC kinases revealed that all three AKT isoforms express alternative transcripts lacking the HM regulatory motif, which was not the case for SGK1-3, S6K1-2, and classical, novel and atypical PKC isoforms. The transcripts of splice variants of Akt1-3 excluding the HM regulatory region could lead to expression of deregulated forms of AKT.
Objectives: Multidrug-resistant organisms (MDRO) are considered an emerging threat worldwide. Data covering the clinical impact of MDRO colonization in patients with solid malignancies, however, is widely missing. We sought to determine the impact of MDRO colonization in patients who have been diagnosed with Non-small cell lung cancer (NSCLC) who are at known high-risk for invasive infections.
Materials and methods: Patients who were screened for MDRO colonization within a 90-day period after NSCLC diagnosis of all stages were included in this single-center retrospective study.
Results: Two hundred and ninety-five patients were included of whom 24 patients (8.1%) were screened positive for MDRO colonization (MDROpos) at first diagnosis. Enterobacterales were by far the most frequent MDRO detected with a proportion of 79.2% (19/24). MDRO colonization was present across all disease stages and more present in patients with concomitant diabetes mellitus. Median overall survival was significantly inferior in the MDROpos study group with a median OS of 7.8 months (95% CI, 0.0–19.9 months) compared to a median OS of 23.9 months (95% CI, 17.6–30.1 months) in the MDROneg group in univariate (p = 0.036) and multivariate analysis (P = 0.02). Exploratory analyses suggest a higher rate of non-cancer-related-mortality in MDROpos patients compared to MDROneg patients (p = 0.002) with an increased rate of fatal infections in MDROpos patients (p = 0.0002).
Conclusions: MDRO colonization is an independent risk factor for inferior OS in patients diagnosed with NSCLC due to a higher rate of fatal infections. Empirical antibiotic treatment approaches should cover formerly detected MDR commensals in cases of (suspected) invasive infections.
Nomadic movements are often a consequence of unpredictable resource dynamics. However, how nomadic ungulates select dynamic resources is still understudied. Here we examined resource selection of nomadic Mongolian gazelles (Procapra gutturosa) in the Eastern Steppe of Mongolia. We used daily GPS locations of 33 gazelles tracked up to 3.5 years. We examined selection for forage during the growing season using the Normalized Difference Vegetation Index (NDVI). In winter we examined selection for snow cover which mediates access to forage and drinking water. We studied selection at the population level using resource selection functions (RSFs) as well as on the individual level using step-selection functions (SSFs) at varying spatio-temporal scales from 1 to 10 days. Results from the population and the individual level analyses differed. At the population level we found selection for higher than average NDVI during the growing season. This may indicate selection for areas with more forage cover within the arid steppe landscape. In winter, gazelles selected for intermediate snow cover, which may indicate preference for areas which offer some snow for hydration but not so much as to hinder movement. At the individual level, in both seasons and across scales, we were not able to detect selection in the majority of individuals, but selection was similar to that seen in the RSFs for those individuals showing selection. Difficulty in finding selection with SSFs may indicate that Mongolian gazelles are using a random search strategy to find forage in a landscape with large, homogeneous areas of vegetation. The combination of random searches and landscape characteristics could therefore obscure results at the fine scale of SSFs. The significant results on the broader scale used for the population level RSF highlight that, although individuals show uncoordinated movement trajectories, they ultimately select for similar vegetation and snow cover.
Our aim was to evaluate the efficacy and toxicity of interstitial multicatheter high dose rate brachytherapy (imHDR- BRT) as accelerated partial breast irradiation (APBI) after second breast-conserving surgery (BCS) in patients with ipsilateral breast tumor recurrence (IBTR). Between January 2010 and December 2019, 20 patients with IBTR who refused salvage mastectomy (sMT) were treated with second BCS and post-operative imHDR-BRT as APBI. All patients had undergone primary BCS followed by adjuvant external beam radiotherapy. Median imHDR-BRT dose was 32 Gy delivered in twice-daily fractions of 4 Gy. Five-year IBTR-free survival, distant metastasis-free survival (DMFS), overall survival (OS) as well as toxicity and cosmesis were evaluated in the present retrospective analysis. Median age at recurrence and median time from the first diagnosis to IBTR was 65.1 years and 12.2 years, respectively. After a median follow-up of 69.9 months, two patients developed a second local recurrence resulting in 5-year IBTR free-survival of 86.8%. Five-year DMFS and 5-year OS were 84.6% and 92.3%, respectively. Grade 1–2 fibrosis was noted in 60% of the patients with no grade 3 or higher toxicity. Two (10%) cases of asymptomatic fat necrosis were documented. Cosmetic outcome was classified as excellent in 6 (37.5%), good in 6 (37.5%), fair in 3 (18.75%) and poor in 1 (6.25%) patient, respectively. We conclude that imHDR-BRT as APBI re-irradiation is effective and safe for IBTR and should be considered in appropriately selected patients.
Most countries affected by the COVID-19 pandemic have repeatedly restricted public life to control the contagion. However, the health impact of confinement measures is hitherto unclear. We performed a multinational survey investigating changes in mental and physical well-being (MWB/PWB) during the first wave of the pandemic. A total of 14,975 individuals from 14 countries provided valid responses. Compared to pre-restrictions, MWB, as measured by the WHO-5 questionnaire, decreased considerably during restrictions (68.1 ± 16.9 to 51.9 ± 21.0 points). Whereas 14.2% of the participants met the cutoff for depression screening pre-restrictions, this share tripled to 45.2% during restrictions. Factors associated with clinically relevant decreases in MWB were female sex (odds ratio/OR = 1.20, 95% CI: 1.11–1.29), high physical activity levels pre-restrictions (OR = 1.29, 95% CI 1.16–1.42), decreased vigorous physical activity during restrictions (OR = 1.14, 95% CI: 1.05–1.23), and working (partially) outside the home vs. working remotely (OR = 1.29, 95% CI: 1.16–1.44/OR = 1.35, 95% CI: 1.23–1.47). Reductions, although smaller, were also seen for PWB. Scores in the SF-36 bodily pain subscale decreased from 85.8 ± 18.7% pre-restrictions to 81.3 ± 21.9% during restrictions. Clinically relevant decrements of PWB were associated with female sex (OR = 1.62, 95% CI: 1.50–1.75), high levels of public life restrictions (OR = 1.26, 95% CI: 1.18–1.36), and young age (OR = 1.10, 95% CI: 1.03–1.19). Study findings suggest lockdowns instituted during the COVID-19 pandemic may have had substantial adverse public health effects. The development of interventions mitigating losses in MWB and PWB is, thus, paramount when preparing for forthcoming waves of COVID-19 or future public life restrictions.
Identification and regulation of tomato Serine/Arginine-rich proteins under high temperatures
(2021)
Alternative splicing is an important mechanism for the regulation of gene expression in eukaryotes during development, cell differentiation or stress response. Alterations in the splicing profiles of genes under high temperatures that cause heat stress (HS) can impact the maintenance of cellular homeostasis and thermotolerance. Consequently, information on factors involved in HS-sensitive alternative splicing is required to formulate the principles of HS response. Serine/arginine-rich (SR) proteins have a central role in alternative splicing. We aimed for the identification and characterization of SR-coding genes in tomato (Solanum lycopersicum), a plant extensively used in HS studies. We identified 17 canonical SR and two SR-like genes. Several SR-coding genes show differential expression and altered splicing profiles in different organs as well as in response to HS. The transcriptional induction of five SR and one SR-like genes is partially dependent on the master regulator of HS response, HS transcription factor HsfA1a. Cis-elements in the promoters of these SR genes were predicted, which can be putatively recognized by HS-induced transcription factors. Further, transiently expressed SRs show reduced or steady-state protein levels in response to HS. Thus, the levels of SRs under HS are regulated by changes in transcription, alternative splicing and protein stability. We propose that the accumulation or reduction of SRs under HS can impact temperature-sensitive alternative splicing.
The thymus hosts the development of a specific type of adaptive immune cells called T cells. T cells orchestrate the adaptive immune response through recognition of antigen by the highly variable T-cell receptor (TCR). T-cell development is a tightly coordinated process comprising lineage commitment, somatic recombination of Tcr gene loci and selection for functional, but non-self-reactive TCRs, all interspersed with massive proliferation and cell death. Thus, the thymus produces a pool of T cells throughout life capable of responding to virtually any exogenous attack while preserving the body through self-tolerance. The thymus has been of considerable interest to both immunologists and theoretical biologists due to its multi-scale quantitative properties, bridging molecular binding, population dynamics and polyclonal repertoire specificity. Here, we review experimental strategies aimed at revealing quantitative and dynamic properties of T-cell development and how they have been implemented in mathematical modeling strategies that were reported to help understand the flexible dynamics of the highly dividing and dying thymic cell populations. Furthermore, we summarize the current challenges to estimating in vivo cellular dynamics and to reaching a next- generation multi-scale picture of T-cell development.
Background: International travel is a major driver of the introduction and spread of SARS- CoV-2. Aim: To investigate SARS-CoV-2 genetic diversity in the region of a major transport hub in Germany, we characterized the viral sequence diversity of the SARS-CoV-2 variants circulating in Frankfurt am Main, the city with the largest airport in Germany, from the end of October to the end of December 2020. Methods: In total, we recovered 136 SARS-CoV-2 genomes from nasopharyngeal swab samples. We isolated 104 isolates that were grown in cell culture and RNA from the recovered viruses and subjected them to full-genome sequence analysis. In addition, 32 nasopharyngeal swab samples were directly sequenced. Results and conclusion: We found 28 different lineages of SARS- CoV-2 circulating during the study period, including the variant of concern B.1.1.7 (∆69/70, N501Y). Six of the lineages had not previously been observed in Germany. We detected the spike protein (S) deletion ∆69/∆70 in 15% of all sequences, a four base pair (bp) deletion (in 2.9% of sequences) and a single bp deletion (in 0.7% of sequences) in ORF3a, leading to ORF3a truncations. In four sequences (2.9%), an amino acid deletion at position 210 in S was identified. In a single sample (0.7%), both a 9 bp deletion in ORF1ab and a 7 bp deletion in ORF7a were identified. One sequence in lineage B.1.1.70 had an N501Y substitution while lacking the ∆69/70 in S. The high diversity of sequences observed over two months in Frankfurt am Main highlights the persisting need for continuous SARS-CoV-2 surveillance using full-genome sequencing, particularly in cities with international airport connections.
Macrophages supply iron to the breast tumor microenvironment by enforced secretion of lipocalin-2 (Lcn-2)-bound iron as well as the increased expression of the iron exporter ferroportin (FPN). We aimed at identifying the contribution of each pathway in supplying iron for the growing tumor, thereby fostering tumor progression. Analyzing the expression profiles of Lcn-2 and FPN using the spontaneous polyoma-middle-T oncogene (PyMT) breast cancer model as well as mining publicly available TCGA (The Cancer Genome Atlas) and GEO Series(GSE) datasets from the Gene Expression Omnibus database (GEO), we found no association between tumor parameters and Lcn-2 or FPN. However, stromal/macrophage-expression of Lcn-2 correlated with tumor onset, lung metastases, and recurrence, whereas FPN did not. While the total iron amount in wildtype and Lcn-2−/− PyMT tumors showed no difference, we observed that tumor-associated macrophages from Lcn-2−/− compared to wildtype tumors stored more iron. In contrast, Lcn-2−/− tumor cells accumulated less iron than their wildtype counterparts, translating into a low migratory and proliferative capacity of Lcn-2−/− tumor cells in a 3D tumor spheroid model in vitro. Our data suggest a pivotal role of Lcn-2 in tumor iron-management, affecting tumor growth. This study underscores the role of iron for tumor progression and the need for a better understanding of iron-targeted therapy approaches.
There are longstanding calls for international organizations (IOs) to be more inclusive of the voices and interests of people whose lives they affect. There is nevertheless widespread disagreement among practitioners and political theorists over who ought to be included in IO decision-making and by what means. This paper focuses on the inclusion of IOs’ ‘intended beneficiaries,’ both in principle and practice. It argues that IOs’ intended beneficiaries have particularly strong normative claims for inclusion because IOs can affect their vital interests and their political agency. It then examines how these claims to inclusion might be feasibly addressed. The paper proposes a model of inclusion via representation and communication, or ‘mediated inclusion.’ An examination of existing practices in global governance reveals significant opportunities for the mediated inclusion of IOs’ intended beneficiaries, as well as pervasive obstacles. The paper concludes that the inclusion of intended beneficiaries by IOs is both appropriate and feasible.
Background: Mesenchymal stromal cells (MSCs), multipotent progenitors that can be isolated from a variety of different tissues, are becoming increasingly important as cell therapeutics targeting immunopathologies and tissue regeneration. Current protocols for MSC isolation from bone marrow (BM) rely on density gradient centrifugation (DGC), and the production of sufficient MSC doses is a critical factor for conducting clinical MSC trials. Previously, a Good Manufacturing Practice (GMP)–compatible non-woven fabric filter device system to isolate MSCs was developed to increase the MSC yield from the BM. The aim of our study was to compare high-resolution phenotypic and functional characteristics of BM-MSCs isolated with this device and with standard DGC technology.
Methods: Human BM samples from 5 donors were analyzed. Each sample was divided equally, processing by DGC, and with the filter device. Stem cell content was assessed by quantification of colony-forming units fibroblasts (CFU-F). Immunophenotype was analyzed by multicolor flow cytometry. In vitro trilineage differentiation potential, trophic factors, and IDO-1 production were assessed. Functionally, immunomodulatory potential, wound healing, and angiogenesis were assayed in vitro.
Results: The CFU-F yield was 15-fold higher in the MSC preparations isolated with the device compared to those isolated by DGC. Consequently, the MSC yield that could be manufactured at passage 3 per mL collected BM was more than 10 times higher in the device group compared to DGC (1.65 × 109 vs. 1.45 × 108). The immunomodulatory potential and IDO-1 production showed donor-to-donor variabilities without differences between fabric filter-isolated and DGC-isolated MSCs. The results from the wound closure assays, the tube formation assays, and the trilineage differentiation assays were similar between the groups with respect to the isolation method. Sixty-four MSC subpopulations could be quantified with CD140a+CD119+CD146+ as most common phenotype group, and CD140a+CD119+CD146+MSCA-1–CD106–CD271– and CD140a+CD119+CD146–MSCA-1–CD106–CD271– as most frequent MSC subpopulations. As trophic factors hepatocyte growth factor, epidermal growth factor, brain-derived neurotrophic factor, angiopoietin-1, and vascular endothelial growth factor A could be detected in both groups with considerable variability between donors, but independent of the respective MSC isolation technique.
Conclusion: The isolation of MSCs using a GMP-compatible fabric filter system device resulted in higher yield of CFU-F, producing substantially more MSCs with similar subpopulation composition and functional characteristics as MSCs isolated by DGC.
Reduced social functioning in depression has been explained by different factors. Reduced social connectedness and prosocial motivation may contribute to interpersonal difficulties, particularly in chronic depression. In the present study, we tested whether social connectedness and prosocial motivation are reduced in chronic depression. Forty-seven patients with persistent depression and 49 healthy controls matched for age and gender completed the Inclusion of the Other in the Self Scale (IOS), the Compassionate Love Scale (CLS), the Beck Depression Inventory-II, and the Childhood Trauma Questionnaire. A Multivariate analysis of variance (MANOVA) with IOS and CLS as dependent variables revealed a highly significant difference between both groups. The IOS and the CLS-subscale Close Others were lower in persistent depression, whereas there was no difference in the CLS-subscale Strangers/Humanity. IOS and CLS-Close Others showed significant negative correlations with depressive symptoms. Connectedness to family members as measured by the IOS was negatively correlated with childhood trauma in patients with chronic depression. The results indicate that compassion and perceived social connection are reduced in depressed patients toward close others, but not to others in general. Implications for the treatment of depression are discussed.